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Publication Abstract from PubMed

High-potency 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are usually featured by time-dependent inhibition. However, the molecular mechanism underlying time-dependent inhibition by HPPD inhibitors has not been fully elucidated. Here, based on the determination of the HPPD binding mode of natural products, the pi-pi sandwich stacking interaction was found to be a critical element determining time-dependent inhibition. This result implied that, for the time-dependent inhibitors, strengthening the pi-pi sandwich stacking interaction might improve their inhibitory efficacy. Consequently, modification with one methyl group on the bicyclic ring of quinazolindione inhibitors was achieved, thereby strengthening the stacking interaction and significantly improving the inhibitory efficacy. Further introduction of bulkier hydrophobic substituents with higher flexibility resulted in a series of HPPD inhibitors with outstanding subnanomolar potency. Exploration of the time-dependent inhibition mechanism and molecular design based on the exploration results are very successful cases of structure-based rational design and provide a guiding reference for future development of HPPD inhibitors.

Discovery of Subnanomolar Inhibitors of 4-Hydroxyphenylpyruvate Dioxygenase via Structure-Based Rational Design.,Dong J, Dong J, Yu XH, Yan YC, Nan JX, Ye BQ, Yang WC, Lin HY, Yang GF J Agric Food Chem. 2023 Jan 18;71(2):1170-1177. doi: 10.1021/acs.jafc.2c06727. , Epub 2023 Jan 4. PMID:36599124^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.